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Corresponding author at: Department of Neurology, Oslo University Hospital – Rikshospitalet, PO Box 4950, Nydalen, 0424 Oslo, Norway. Tel.: +47 23072762.
Complex, bidirectional interdependence between sex steroid hormones and epilepsy.
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Progesterone and its metabolites are anticonvulsant, estrogens mainly proconvulsant.
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Androgens are mainly anticonvulsant, but the effects are more varied.
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Sex steroid hormones affect brain excitability mainly through membrane receptors.
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Epileptic activity, especially mediated via amygdala, alters reproductive function.
Abstract
There is a complex, bidirectional interdependence between sex steroid hormones and epilepsy; hormones affect seizures, while seizures affect hormones thereby disturbing reproductive endocrine function.
Both female and male sex steroid hormones influence brain excitability. For the female sex steroid hormones, progesterone and its metabolites are anticonvulsant, while estrogens are mainly proconvulsant. The monthly fluctuations in hormone levels of estrogen and progesterone are the basis for catamenial epilepsy described elsewhere in this issue. Androgens are mainly anticonvulsant, but the effects are more varied, probably because of its metabolism to, among others, estradiol.
The mechanisms for the effects of sex steroid hormones on brain excitability are related to both classical, intracellularly mediated effects, and non-classical membrane effects due to binding to membrane receptors. The latter are considered the most important in relation to epilepsy. The different sex steroids can also be further metabolized within the brain to different neurosteroids, which are even more potent with regard to their effect on excitability. Estrogens potentiate glutamate responses, primarily by potentiating NMDA receptor activity, but also by affecting GABA-ergic mechanisms and altering brain morphology by increasing dendritic spine density. Progesterone and its main metabolite 5α-pregnan-3α-ol-20-one (3α-5α-THP) act mainly to enhance postsynaptic GABA-ergic activity, while androgens enhance GABA-activated currents.
Seizures and epileptic discharges also affect sex steroid hormones. There are close anatomical connections between the temporolimbic system and the hypothalamus controlling the endocrine system. Several studies have shown that epileptic activity, especially mediated through the amygdala, alters reproductive function, including reduced ovarian cyclicity in females and altered sex steroid hormone levels in both genders. Furthermore, there is an asymmetric activation of the hypothalamus with unilateral amygdala seizures. This may, again, be the basis for the occurrence of different reproductive endocrine disorders described for patients with left-sided or right-sided temporal lobe epilepsy.
There is a complex interaction between hormones and epilepsy that is manifest in many different ways. Firstly, hormones influence epilepsy, while secondly, epilepsy affects hormones. In addition, antiepileptic drugs (AEDs) can interact both with the epilepsy itself and with hormones. The focus of this review is hormones and gender, addressing the interactions between epilepsy and sex steroid hormones. Interactions with AEDs are described elsewhere in this issue of Seizure, which is a special issue based on presentations held at the Second Gender Issues in Epilepsy Meeting in Oslo, 28–29 August 2014.
The male and female peripheral sex steroid hormones, estradiol, progesterone, and testosterone, are all derived from cholesterol and are closely linked as seen in Fig. 1. Cholesterol, having been metabolized to progesterone, can be further metabolized to androstenedione and testosterone. These, in turn, through aromatization can be transformed to estradiol. Furthermore, progesterone is metabolized through the action of the enzymes 5α-reductase and 3α-hydroxysteroid to 3α-5α-THP, a very powerful antiepileptogenic substance. Steroids that are synthesized in the brain are also called neurosteroids; they are precursors and metabolites of steroid hormones influencing neuronal excitability, mainly through non-genomic mechanisms. The enzymes 5α-reductase and 3α -hydroxysteroid, the most important enzymes enabling the brain to produce neurosteroids, are widely distributed in the brain.
Fig. 1Formation of progesterone and its metabolites, estrogens, and testosterone from cholesterol.
Published with permission from: Frye CA, Rhodes ME. Female sex steroids and neuronal excitability. In: Schwartzkroin PA, editor. Encyclopedia of basic epilepsy research. UK: Academic Press/Elsevier; 2009, p. 477–84.
Clinically, the effect of hormones on brain excitability appear as fluctuations in seizure frequency in relation to changes in hormone levels. This is most typically seen in catamenial epilepsy [
], where seizure frequency varies with fluctuations in estrogen and progesterone levels (Fig. 2). The phenomenon of cyclical changes in seizure frequency in relation to menstruation was first properly studied by Gowers [
] in 1885, who found a relationship between menstrual phases and seizure frequency in 46 of 82 patients. This finding was later confirmed in numerous studies, like that of Laidlaw [
] who monitored 50 institutionalized patients and demonstrated seizure exacerbation in relation to menstruation in 72% of the women. The phenomenon of catamenial epilepsy demonstrates the clinical relevance of hormonal effects on brain excitability.
Fig. 2Cross-correlogram between menstrual status and seizure occurrence in a patient with catamenial epilepsy. Note the marked, local positive peaks occurring every 4 weeks, indicating a high incidence of co-occurrence of seizures and menstruation.
Published with permission from: Taubøll E, Lundervold A, Gjerstad L. Temporal distribution of seizures in epilepsy. Epilepsy Res 1991;8:153–65.
Female sex steroid hormones have repeatedly been shown to affect neuronal excitability, with estrogens being mainly proconvulsant and progesterone and its metabolites being anticonvulsant.
Clinically, a direct excitatory effect of estrogen was convincingly demonstrated by Logothetis et al. in 1959 [
]. Intravenous (i.v.) injections of the estrogenic substance, Premarin, were administered to 16 female epileptic patients, of whom eleven patients showed increased epileptogenic activity and four experienced frank seizures (Fig. 3). Of the four patients that received the highest dose, three patients experienced fits, indicating a dose-dependent effect of estrogen on seizure excitability. In contrast to estrogen, progesterone infusions in epilepsy patients reduce seizure susceptibility. Bäckström et al. [
] studied seven female patients with partial epilepsy who received a 2-h i.v. infusion of progesterone during the first week of their menstrual cycles. The progesterone infusions reached plasma concentrations during the luteal phase. Four of the patients showed significant decreases in spike frequency during the infusion, with a latency of 1–2 h. The two patients demonstrating the most pronounced effect showed the lowest progesterone binding capacity, while the patients not showing any effect had the highest binding capacity. Thus, the effect seems to be related to the concentrations of free hormone. Similar clinical human studies as described for progesterone and estradiol have not been performed with testosterone.
Fig. 3EEG in a patient with epilepsy during estrogen (Premarin) injection leading to seizure.
Published with permission from: Logothetis J, Harner R, Morrell F, Torres F. The role of estrogens in catamenial exacerbation of epilepsy. Neurology 1959;9:352–60.
The results from these clinical studies have been supported by several animal studies that have demonstrated increased seizure frequency after estrogen administration, and decreased seizure frequency after progesterone injections. Estrogen administered as injections [
]). Estradiol also reduces electroshock threshold, increases paroxysmal spiking in epileptogenic foci in cats and rabbits, facilitates kindling, and potentiates seizures induced by different chemoconvulsants [
]. Administration of androgens directly to the hippocampus of castrated rats reduces PTZ-induced seizures, and testosterone increases the electroconvulsive threshold in males at low doses, and in both sexes at higher doses [
There are three biologically active estrogens, as seen in Fig. 1. Estradiol is the main estrogen in fertile women and has been studied the most. Estriol is the major estrogen in pregnancy, while estrone is most abundant in postmenopausal women.
Mechanisms involved in the excitatory effect of estrogens are complex, and in some circumstances estrogens may even be anticonvulsant. Estrogens, as the other peripheral sex steroid hormones, exert their effects via intracellular receptors, the estrogen receptors ERα and ERβ, of which the effect of the latter is the most important for the non-reproductive effects of the hormone. Some experiments have found that low estrogen doses may actually reduce seizures by acting at ERβ [
In general, however, the effect of estrogens should be considered excitatory. Important for the generally excitatory effect, is the ability of neurons to respond rapidly to the excitatory effect of glutamate [
]. Using extracellular recordings from single Purkinje cells in rat cerebellum, systemic injections of estradiol produced a marked enhancement of the excitatory response to iontophoretically applied glutamate. The effect was dose-dependent. Very similar results were obtained with local application. Typically, enhancement of glutamate excitation was noted within 40 s after onset of local steroid application.
GABA-ergic mechanisms, however, do not seem to be affected as an acute response. In a study using both hippocampal slices from rats of both sexes and an in vivo cat cervaux isole model using female cats [
] we could not detect any acute effect of 17β estradiol on synaptic activation or seizure generation. Also, more specific investigations of possible effects on GABA responses using iontophoretically applied GABA, before and after estrogen perfusion, did not identify any change. This is in line with other studies that have not shown any effect of estradiol on GABA-ergic inhibition in Purkinje cerebellar cells [
]. However, all these experiments were done with non-epileptic tissue that was supposed to have intact inhibitory mechanisms. Nevertheless, the findings agree with the early reports [
] in which spontaneous cortical electrical activity in healthy animals was found to be unchanged after i.v. injections of estrogens. In order to produce epileptogenic activity, the estrogenic substance, Premarin, had to be given to animals with both an epileptic focus and a focal lesion of the blood–brain barrier. Therefore, it is possible that patients with focal epilepsy might be much more susceptible to changes in brain estradiol levels than healthy controls.
Estrogens also affect the GABA-ergic system over time. In a series of studies by Woolley [
] it was shown that longer exposure (greater than 24 h) to estradiol leads to suppressed GABA-ergic inhibition of hippocampal neurons that may be related to decreased GABA release at inhibitory synapses. In addition, it is assumed that estradiol decreases GABA synthesis by reducing the activity of glutamate decarboxylase (GAD) in the amygdala [
], where changes in GAD activity in the cortex, hippocampus, and substantia nigra were not detected.
Estradiol has also been found to alter brain morphology by increasing dendritic spine density via an NMDA receptor-dependent mechanism, and altering the pattern of hippocampal synaptic connectivity [
]. Estradiol selectively increased neuronal sensitivity to synaptic input mediated by the NMDA type of glutamate receptor, while responses mediated by the AMPA receptor were not affected. Ovariectomy caused spine density to decrease. These continuous, plastic changes in morphology, which are related to spine density and neuronal sensitivity to glutamate are probably of utmost importance for the effects of estrogen on brain excitability.
One last point regarding the effect of estradiol, is the possibility of regional differences. In the 1960s, Timiras and coworkers [
] found that estradiol decreased seizure threshold in the dorsal hippocampus and the medial amygdala, but simultaneously increased seizure threshold in the lateral amygdala. Furthermore, in rat medial amygdala brain slices, estradiol hyperpolarized 19 of 70 neurons from ovariectomized females. However, this effect was highly regional as no effect was observed in 36 neurons of the basolateral amygdala [
The mechanisms by which progesterone and its metabolites exert their effects on brain excitability are, as for estrogens, also through both classical and non-classical mechanisms, with the latter being by far the most important. Progesterone receptors are widely distributed in the brain [
]. Production of this very effective anticonvulsant neurosteroid can therefore take place in many regions of the brain. The antiepileptic effect of progesterone is mainly attributed to its conversion to 3α-5α-THP. Therefore, the anticonvulsant effect of progesterone in the brain in in vivo models is somewhat delayed in comparison with the immediate effect of its metabolite 3α-5α-THP (Fig. 4).
Fig. 4Changes in electroshock seizure thresholds after i.v. injections of 3α-5α-THP (=3α-OH-DHP) (A), progesterone (B) and the solvent Glycofurol (C). Vertical bars represent injections periods. Open circles represent stimulation trials that were subthreshold for seizure initiation, filled circles trials followed by seizures. Note the threshold increase after both 3α-5α-THP and progesterone, but also the difference in time course with an immediate effect after 3α-5α-THP with a more delayed effect after progesterone.
Published with permission from: Taubøll E, Lindström S. The effect of progesterone and its metabolite 5α-pregnan-3α-ol-20-one on focal epileptic seizures in the cat's visual cortex in vivo. Epilepsy Res 1993;14:17–30.
The main effect of 3α-5α-THP is related to an enhanced postsynaptic GABA-ergic effect, as based on several lines of evidence. 3α-5α-THP increases the inward chloride current induced by GABA [
Longer term progesterone treatment induces changes of GABA-A receptor levels in forebrain sites in the female hamster: quantitative autoradiography study.
Effects of pemtobarbital on t-[35S]butylbicyclophosphorithionate and [3H]flunitrazepam binding to membrane-bound and solubilized preparations from rat forebrain.
] that demonstrated how the metabolite significantly and dose-dependently increased both the peak amplitude and duration of the inward chloride current induced by GABA [
]. In line with this, we were also able to demonstrate the effect both of progesterone, and especially its metabolite, 3α-5α-THP, on recurrent GABA-ergic inhibition in rat hippocampal slices [
How the effect on GABA-ergic induced chloride influx is exerted and exactly where the steroid binds to the GABA receptor complex has been discussed. With regard to the effect on chloride influx, it was shown early on that this was mainly related to an increase in the effective open-time of the chloride channels, as is also the case for barbiturates [
The binding site for progesterone metabolites differs from that of both barbiturates and benzodiazepines. With regard to the barbiturate site, it has been shown that 3α-5α-THP and barbiturates both potentiate each other in their ability to accelerate the dissociation of TBPS [
]. Thus, steroid metabolites and barbiturates do not seem to share the same site on the GABA receptor. With regard to the benzodiazepine receptor, several lines of evidence demonstrate that steroid metabolites do not act via an interaction with the benzodiazepine recognition site [
]. There is therefore a unique binding site for neurosteroids within the GABA-A receptor complex that is not directly related to either the barbiturate site or the benzodiazepine site.
In addition to these postsynaptic GABA-ergic effects, which are definitely the most important, there has been some discussion on whether there could also be an additional presynaptic effect. Our in vivo studies in the cat cervau isolé preparation suggested that 3α-5α-THP might also exert some presynaptic effects [
], as both the monosynaptic and disynaptic components of the uninhibited excitatory field potential were reduced. This mimics the effect of barbiturates in the same system, which, in addition to an effect on postsynaptic inhibition, also acts presynaptically, by reducing the transmitter release. In a study of monosynaptic excitatory transmission in the spinal cord, the barbiturate-reduced transmitter release was associated with a small decrease in the presynaptic nerve volley [
]. An effect on transmitter release is also indicated in Fig. 5, where the amplitude of the monosynaptic component of the field excitatory potential in the dorsal lateral geniculate nucleus was plotted against stimulus current or against the amplitude of the incoming nerve volley (Fig. 5). The slope decreased after exposure to 3α-5α-THP. The most likely explanation for this finding is a change in transmitter release. A possible presynaptic additional effect also gains some support from our study showing reduced GABA and glutamate release from nerve terminals in rat hippocampus, although concentrations were above clinical levels [
The progesterone metabolite 5α-pregnan-3α-ol-20-one reduces the K+-induced GABA and glutamate release from identified nerve terminals in rat hippocampus: a semiquantitative immunocytochemical study.
]. The clinical relevance of a possible presynaptic effect is, however, uncertain.
Fig. 5The amplitude of the monosynaptic component of the field excitatory potential in the dorsal Lateral Geniculate Nucleus in the cat plotted against stimulus current and the amplitude of the incoming nerve volley.
Data from Taubøll E, Lindström S. The effect of progesterone and its metabolite 5α-pregnan-3α-ol-20-one on focal epileptic seizures in the cat's visual cortex in vivo. Epilepsy Res 1993;14:17–30 (figure not previously published).
In addition to an effect on GABA responses, progesterone and its metabolites may also affect excitatory mechanisms. In a series of studies utilizing Purkinje cells from rat cerebellum, it was shown that both progesterone itself and several of its metabolites, including 3α-5α-THP, decreased glutamate responsiveness after either systemic or topical application [
Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters.
]. Further, progesterone metabolites like 3α-5α-THP act at the NMDA receptor, affecting at least sexual behavior, but probably also brain excitability [
Little is known regarding the ability of progesterone metabolites to affect neuronal morphology directly, as has been demonstrated for the estrogens. However, it has at least been found that chronic progesterone treatment of adult male rats resulted in a 30% increase in the density of central benzodiazepine receptors in the cerebral cortex, but not in the hippocampus [
Another way of affecting seizure susceptibility is by altering the subunit composition of the GABA-A receptor. This may be of importance for catamenial epilepsy and for its treatment. The most striking finding following progesterone withdrawal, a model for catamenial epilepsy, is the marked up-regulation of the alfa-4 subunit of the GABA receptor [
Withdrawal from 3alpha-OH-5alpha-pregnan-20-one using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor alpha4 subunit in association with increased anxiety.
Progesterone withdrawal increases the alpha4 subunit of the GABA(A) receptor in male rats in association with anxiety and altered pharmacology – a comparison with female rats.
]. This subunit is insensitive to benzodiazepines. The increase in alfa-4 expression also leads to a decrease in inhibition gated by the GABA-A receptor [
]. By dynamically changing GABA receptor subunit composition in situations with progesterone withdrawal, which is the case premenstrually, seizure threshold and sensitivity to AED treatment will also vary on a cyclic basis. This can then contribute to the phenomenon of catamenial epilepsy. In this context, it is of interest that at least some neurosteroids may be able to modulate all isoforms of GABA-A receptors, including those containing the alfa-4 subunit. This provides possibilities for a new drug such as Ganaxalone, for specific treatment of women with catamenial epilepsy; Ganaxalone is, in essence, a neurosteroid, but also acts at the alfa-4 subunit.
Although the effects on non-classical mechanisms are by far the most important for the role of progesterone and its metabolites as anticonvulsants, a possible effect on intracellular, classical progesterone receptors cannot be completely excluded. In a series of experiments, mainly on PTZ-induced seizures in ovariectomized rats, a possible role for classical progesterone receptors as being relevant for the anticonvulsant effect was demonstrated [
]. It was shown that both progesterone, which acts both at the intracellular level and after conversion to its metabolites at the membrane receptor, and RU5020, which only acts at the intracellular progesterone receptor, both markedly reduce tonic-clonic seizures. When progesterone and especially RU5020 were co-administered with RU38486, which blocks the intracellular progesterone receptor, the anticonvulsant effect of the drugs was considerably reduced (Fig. 6). These experiments suggest that intracellular progesterone receptors may also be involved, at least to some degree, in the anticonvulsant effect of progesterone and its metabolites.
Fig. 6Average number of seizures after pentylenetetrazol in ovariectomized rats administered vehicle, progesterone, RU5020, 3α-5α-THP, progesterone +RU486, RU5020 + RU486, 3α-5α-THP + RU486 or RU486. See text for discussion.
Published with permission from: Frye CA, Rhodes ME. Female sex steroids and neuronal excitability. In: Schwartzkroin PA, editor. Encyclopedia of basic epilepsy research. UK: Academic Press/Elsevier; 2009. p. 477–84.
The effects of androgens are mainly anticonvulsant, but the opposite can also be the case. The variable actions of testosterone may be partly due to the metabolism of testosterone. Testosterone can be metabolized to 17β-estradiol, which is generally excitatory, but also to androstandediol and dihydrotestosterone, which exert potent antiepileptic effects [
As with the other sex steroids, androgens act via both classical and non-classical mechanisms. The effect on classical mechanisms is demonstrated by the proconvulsant effect of flutamide, an antagonist of the intracellular androgen receptor. In addition, it has been shown that testicular feminized mice, which are totally insensitive to androgens due to mutations in the intracellular androgen receptor, do not exhibit the antiseizure effects of androgens produced in wild-type animals [
] showed that androstanediol produced a concentration-dependent enhancement of GABA-activated currents. At 1 μM, androstanediol produced a 50% potentiation of GABA responses. In the absence of GABA, androstanediol had moderate direct effects on GABA-A receptor-mediated currents at high concentrations. Systemic doses of androstanediol (5–100 mg/kg), but not its 3β-variant, caused dose-dependent suppression of behavioral and electrographic seizures in a mouse hippocampal kindling model, which is a model of temporal lobe epilepsy. At high doses, androstanediol produced complete seizure protection that lasted for up to 3 h after injection.
Androgens also have effects on neuronal structure and function. Testosterone application to gonadectomized male rats increases the number of spine synapses in the stratum radiatum of area CA1 in the hippocampus [
]. Androgens may also affect spine synapse density in the hippocampus in female rats and contribute to plastic changes over the course of the menstrual cycle [
]. The importance for epilepsy of these findings of altered morphology with regard to the androgens is still uncertain.
6. The effects of epilepsy on endocrine function
Reproductive dysfunction and endocrine disorders are common among both men and women with epilepsy, indicating an effect of the epilepsy itself. In women, menstrual disorders, polycystic ovaries, hypothalamic amenorrhea, premature menopause, and reduced fertility have been described, while in men reduced potency and sperm abnormalities have been found [
]. In both sexes, sexual problems like diminished sexual desire, reduced sexual responsiveness, orgasmic dysfunctions, as well as reduced genital blood flow in women and ejaculation disorders in men have been described [
The reasons for the changes in reproductive endocrine function are, however, multifactorial. They include psychosocial factors, co-morbidity, the use of AEDs, and, finally, the epilepsy itself.
Clinically, it is difficult to distinguish the direct effect of epileptic activity, independent of the many confounding factors mentioned above. But results from clinical studies provide indications of a direct effect of epilepsy on reproductive endocrine function. For instance, a greater occurrence of sexual dysfunction has been found in both men and women with right-sided, versus left-sided, temporal epilepsy [
], with sexual interest primarily decreased. Prolactin responses may also reach higher levels in right-sided versus left-sided epileptiform discharges [
]. Finally, studies by Herzog and coworkers have shown that there is laterality in reproductive endocrine function and disorders in women with epilepsy [
], which, in turn, is associated with higher luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratios and higher testosterone levels. This eventually leads to polycystic ovaries, which are found more frequently after left-sided epileptic epilepsy than right-sided epileptic epilepsy. On the other hand, right temporal foci have a reduced GnRH pulse frequency, lower LH and estradiol levels, and a higher frequency of hypothalamic amenorrhea [
]. Such lateralized effects can hardly be attributed to confounding factors like the influence of AEDs, and thus indicate a direct effect of the epilepsy itself on reproductive endocrine function.
In men with temporal epilepsy the pulsatile secretion of LH has been found to be disturbed [
]. Interictally, both circadian and ultradian rhythms were altered with a generally delayed LH peak. Postictally, there was a random dispersal of the timing of the LH peak and prolongation of interburst intervals. The material consisted of only ten patients, seven with left-sided focus and three with right. However, despite the small number of patients, it is interesting that right temporal seizures were associated with LH concentration phase delays and left temporal seizures with advances. Again, such lateralized effects are probably due to the epilepsy itself, not to concomitant medication.
With regard to reproductive endocrine disorders related to different types of epilepsy, there is no convincing evidence that such problems are more common in partial or generalized epilepsies. Some studies have indicated more reproductive and sexual problems in patients with partial epilepsy [
]. Thus we are currently unable to reach firm conclusions regarding associations between epilepsy type and reproductive endocrine problems.
Some of the problems related to clinical studies can be overcome by the use of animal models. Very close anatomical connections between the temporolimbic system and the hypothalamus, which is controlling the neuroendocrine system including both the hypothalamic–pituitary–gonadal and the hypothalamic–pituitary–adrenal axis, have been demonstrated. The amygdala in particular, has massive direct reciprocal connections with regions of the hypothalamus that are involved in the regulation, production, and secretion of GnRH. In line with this, early studies demonstrated how amygdala kindling in male cats led to hyposexuality [
]. These studies demonstrate the close interactions between neuronal hyperactivity or hypoactivity in the temporolimbic brain areas and reproductive endocrine function.
] showed how seizures affected reproductive function in both female and male rats. In females, amygdala-kindled seizures arrested ovarian cyclicity. The animals also had high serum estradiol, increased pituitary weight, and polyfollicular ovaries. Progesterone treatment to kindled females restored cyclicity in only five of 28 (18%) of the animals that had stopped cycling, while all sham-kindled (n = 5) controls that had stopped cycling regained cyclicity. In male rats, amygdala-kindled seizures resulted in an increase in serum testosterone, estradiol, and prolactin in intact males, accompanied by a significant increase in testis, epididymis, and pituitary weight, as well as a significant decrease in prostate weight. Maximal electroshock seizures caused a short-term reduction in serum testosterone and testis, epididymis, and prostate weight. This indicates that both focal limbic (amygdaloid) seizures and generalized maximal electroshock seizures disturb normal reproductive physiology in the male rat.
] showed asymmetric activation of hypothalamic regions after unilateral amygdala-stimulated seizures. Studying Fos-immunoreactivity in different hypothalamic areas, they found that three areas that are prominently involved in reproductive function, the medial preoptic nucleus (MPO), the ventrolateral part of the ventromedial hypothalamus (VMHVL), and the ventral premammillary nucleus (PMV). These areas showed both significantly greater and more asymmetric, ipsilaterally predominating induction of Fos after unilateral amygdala-stimulated seizures than other regions that were investigated, such as sexually undifferentiated regions like the lateral (LPO), medial preoptic area (MPA), the dorsomedial portion of the ventromedial nucleus (VMHDM), and the paraventricular nucleus (PVH), which are involved in other endocrine functions (Fig. 7). Asymmetric activation of the hypothalamus could be the basis for the occurrence of different reproductive endocrine disorders for patients with left-sided or right-sided temporal lobe epilepsy, since the hypothalamus has a clear asymmetry in its reproductive function, including asymmetric content of GnRH [
]. These studies clearly demonstrate a direct effect of epilepsy and epileptic discharges on reproductive endocrine function.
Fig. 7Photomicrographs of hypothalamic nuclei from one right-amygdala-stimulated rat. (A and C) Similar numbers of Fos-ir neurons on the left and right sides of the medial preoptic area (MPA) and paraventricular hypothalamic nucleus (PVH), areas not involved in reproductive endocrine function. (B, D and E) Laterally asymmetric, ipsilaterally predominating numbers of Fos-ir neurons in the medial preoptic nucleus (MPO), ventrolateral part of the ventromedial hypothalamic nucleus (VMH), and in the ventral premamillary nucleus (PMV), areas that are involved in reproductive function and reproductive endocrine secretion.
Published with permission from: Silveira DC, Klein P, Ransil BJ, Liu Z, Hori A, Holmes GL, LaCalle S, Elmquist J, Herzog AG. Lateral asymmetry in activation of hypothalamic neurons with unilateral amygdaloid seizures. Epilepsia 2000;41:34–41.
In conclusion, there is a close interaction between sex steroid hormones and epilepsy. Sex steroid hormones play an important role in neuronal excitability and seizure susceptibility with progesterone and its metabolites being anticonvulsive, with estrogens being mainly proconvulsive. The monthly fluctuations in progesterone and estrogen are thought to be the basis for catamenial epilepsy. Androgens have more varied effects, although considered mainly anticonvulsive. Epilepsy itself, especially through temporolimbic connections, affects the secretion of pituitary hormones thereby affecting secretion pattern, rhythmicity and hormone levels of the peripheral sex steroid hormones. Even laterality of epileptic activity are of importance as there has been shown different endocrine disturbances in patients with left-sided compared to right sided epileptic foci.
Conflict of interest statement
There are no conflicts of interest.
References
Herzog A.G.
Catamenial epilepsy update on pathophysiology, prevalence and treatment from the findings of the NIH Progesterone treatment trial.
Longer term progesterone treatment induces changes of GABA-A receptor levels in forebrain sites in the female hamster: quantitative autoradiography study.
Effects of pemtobarbital on t-[35S]butylbicyclophosphorithionate and [3H]flunitrazepam binding to membrane-bound and solubilized preparations from rat forebrain.
The progesterone metabolite 5α-pregnan-3α-ol-20-one reduces the K+-induced GABA and glutamate release from identified nerve terminals in rat hippocampus: a semiquantitative immunocytochemical study.
Sex steroid effects on extrahypothalamic CNS. II. Progesterone, alone and in combination with estrogen, modulates cerebellar responses to amino acid neurotransmitters.
Withdrawal from 3alpha-OH-5alpha-pregnan-20-one using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor alpha4 subunit in association with increased anxiety.
Progesterone withdrawal increases the alpha4 subunit of the GABA(A) receptor in male rats in association with anxiety and altered pharmacology – a comparison with female rats.
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